This invention relates to a dialysis membrane for hemodialysis in the form of films, tubular films, or hollow filaments made of polysaccharide ethers.
Dialysis membranes for hemodialysis have very stringent requirements with regard to biocompatibility so that the blood flowing through the membranes is damaged as little as possible. Important parameters of biocompatibility are blood coagulation, leukopenia, and complement activation.
DE-OS 35 24 596 has already disclosed a dialysis membrane with improved biocompatibility that is able to reduce blood coagulation, leukopenia, and complement activation to a considerable extent and that is distinguished by modified cellulose whose average degree of substitution is 0.02 to 0.07. The known dialysis membrane made of modified cellulose preferably contains modified cellulose that has a structure represented by the formula EQU Cellulose-R'-X-Y
in which
X stands for -NR"- and/or ##STR2## and/or -S- and/or -SO- and/or -SO.sub.2 - and/or ##STR3## and/or --CO--O--and/or --O--; Y stands for -R and/or -NR.sub.2 and/or -Si(OR").sub.3 ##STR4## R' stands for an alkylene group and/or a cyclo-alkylene group and/or an arylene group with a total of 1 to 25 carbon atoms; PA1 R" stands for a hydrogen atom or R; and PA1 R stands for an alkyl group with 1 to 5 carbon atoms and/or a cycloalkyl group and/or an aryl group.
Besides the fact that dialysis membranes made of synthetic or natural polymers can very easily cause clotting of the blood when used in artificial kidneys, which is largely prevented by appropriate medical treatment, a temporary decrease of leukocytes occurs early in the dialysis treatment of a kidney patient with dialyzers that contain membranes made of regenerated cellulose. This effect is called leukopenia.
Leukopenia is a lowering of the leukocyte count (white blood corpuscles) in the circulatory system. The number of white blood corpuscles in humans is about 4,000 to 12,000 cells/mm.sup.3. Leukopenia is most pronounced 15 to 20 minutes after beginning treatment, at which time the neutrophils (leukocytes that can be stained with neutral or at the same time with acidic and basic dyes) may almost completely disappear. The leukocyte count then increases again in about an hour almost to the initial level, or exceeds it. When a new dialyzer is connected after recovery of the leukocytes, leukopenia again occurs to the same degree.
Cellulose membranes cause pronounced leukopenia. Even though the clinical significance of the leukopenia is not scientifically understood, nevertheless there is a desire for a dialysis membrane for hemodialysis that does not show the effect of leukopenia, without the other very desirable properties of dialysis membranes made of regenerated cellulose thereby being impaired.
In addition to leukopenia, distinct complement activation has also been found during hemodialysis with membranes made of regenerated cellulose. The complement system in the blood is a complex plasma enzyme system consisting of many components that functions in various ways in defending against injuries from invading foreign cells (bacteria and others). When antibodies against the invading organism are present, complement-specific activation can occur from the complex of the antibodies with antigenic structures of the foreign cells; otherwise, complement activation occurs by an alternative pathway through special surface features of the foreign cells. The complement system depends on a number of plasma proteins. After activation, these proteins react specifically with one another in a definite sequence, and at the end, a cell-injuring complex is formed that destroys the foreign cells.
From individual components, peptides are liberated that trigger inflammation and sometimes may also have adverse pathological consequences for the organism. It is assumed that the activation in the case of hemodialysis membranes made of regenerated cellulose occurs by the alternative pathway. These complement activations are determined objectively by determination of the complement fragments C3a and C5a in the plasma.
Reference in this regard is made to the following papers: D. E. Chenoweth et al., Kidney International Vol. 24, pages 764 ff, 1983, and D. E. Chenoweth, Asaio-Journal Vol. 7, pages 44 ff, 1984.
In the context of this invention, complement activation was judged by reference to the C5a fragments. To do this, 300 ml of heparinized blood plasma was recirculated in vitro for a period of 4 hours through a dialyzer with an effective exchange area of 1m.sup.2 with a plasma flow rate of 100 ml/min. The C5a fragments in the plasma were determined by the RIA method (Upjohn test). The relative complement activation for the particular time of measurement was calculated by taking the ratio of the concentration at the time of sampling to the initial value in percent. The value measured after 4 hours of recirculation was used for the evaluation. Membrane films are incubated for 3 hours with heparinized blood plasma and the C5a fragments are then determined.
An increase of the beta-2-microglobulin level in long-term dialysis patients is observed after using membranes made of regenerated cellulose, and is attributed to the fact that these membranes are less permeable in the molecular range of 1,000 to 20,000 and the microglobulins are therefore not sufficiently removed in the dialysis. Beta-2-micro-globulin is not adsorbed to a significant extent on conventional membranes made of regenerated cellulose. However, the cellulose derivatives pursuant to the invention can contribute to this in an unexpected way.
The average degree of polymerization DP was determined in a cuene solution by the method of DIN 54270. The degree of etherification was determined from the results of analysis which are known and typical for the substituents, for example nitrogen by Kjeldahl, sulfur by the Schoniger method, or phosphorus by the molybdate method, when applicable from the difference before and after saponification.
It has recently been found that it is desirable to avoid the heparin adsorption which occurs to a distinct degree particularly with the polysaccharide ethers pursuant to DE-OS 35 24 596. Multiple use of the membrane modules is also desirable to moderate costs, which is naturally reasonable and defensible only when the modules can be cleaned and disinfected perfectly without the desirable properties of the membranes being impaired.
However, in the procedures used up to this time for preparation for reuse, it is precisely the parameters crucial for biocompatibility that have been distinctly impaired, and steam sterilization has led to yellowing of the membranes.